Department of Medical Biochemistry and Microbiology, Uppsala University, BMC Box 582, SE-75123 Uppsala, Sweden.
J Am Chem Soc. 2012 Jan 11;134(1):599-605. doi: 10.1021/ja209341w. Epub 2011 Dec 16.
Intrinsically disordered proteins are very common and mediate numerous protein-protein and protein-DNA interactions. While it is clear that these interactions are instrumental for the life of the mammalian cell, there is a paucity of data regarding their molecular binding mechanisms. Here we have used short peptides as a model system for intrinsically disordered proteins. Linear free energy relationships based on rate and equilibrium constants for the binding of these peptides to ordered target proteins, PDZ domains, demonstrate that native side-chain interactions form mainly after the rate-limiting barrier for binding and in a cooperative fashion. This finding suggests that these disordered peptides first form a weak encounter complex with non-native interactions. The data do not support the recent notion that the affinities of intrinsically disordered proteins toward their targets are generally governed by their association rate constants. Instead, we observed the opposite for peptide-PDZ interactions, namely, that changes in K(d) correlate with changes in k(off).
无规卷曲蛋白非常常见，能介导众多蛋白质-蛋白质和蛋白质-DNA 相互作用。虽然这些相互作用对哺乳动物细胞的生命至关重要，但关于它们的分子结合机制的数据却很少。在这里，我们使用短肽作为无规卷曲蛋白的模型系统。基于这些肽与有序靶蛋白（PDZ 结构域）结合的速率和平衡常数的线性自由能关系表明，天然侧链相互作用主要在结合的速率限制屏障之后以协同的方式形成。这一发现表明，这些无规卷曲肽首先与非天然相互作用形成弱的遭遇复合物。这些数据不支持最近的观点，即无规卷曲蛋白与靶标的亲和力通常由其缔合速率常数决定。相反，我们观察到肽-PDZ 相互作用的情况正好相反，即 K(d)的变化与 k(off)的变化相关。
